Lapachol inhibits glycolysis in cancer cells by targeting pyruvate kinase M2

• Published in: PloS one Vol. 13; no. 2; p. e0191419
• Main Authors: Shankar Babu, Mani, Mahanta, Sailendra, Lakhter, Alexander J, Hato, Takashi, Paul, Subhankar, Naidu, Samisubbu R
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.02.2018; Public Library of Science (PLoS)
• Subjects: Analysis; Apoptosis; Biology and Life Sciences; Cancer; Cancer cells; Cancer therapies; Cell culture; Cell death; Cell proliferation; Glycolysis; Hypoxia; Immunology; Influence; Inhibition; Inhibitors; Laboratories; Medicine; Medicine and Health Sciences; Melanoma; Metabolic pathways; Metabolism; Mitochondria; Oxygen; Oxygen consumption; Physical Sciences; Physiological aspects; Prevention; Properties; Pyruvate kinase; Pyruvic acid; Quinones; Research and Analysis Methods; Shikonin; Tumor cells; United States; Indiana; United States > US; Indianapolis Indiana; India
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0191419

Reliance on aerobic glycolysis is one of the hallmarks of cancer. Although pyruvate kinase M2 (PKM2) is a key mediator of glycolysis in cancer cells, lack of selective agents that target PKM2 remains a challenge in exploiting metabolic pathways for cancer therapy. We report that unlike its structural analog shikonin, a known inhibitor of PKM2, lapachol failed to induce non-apoptotic cell death ferroxitosis in hypoxia. However, melanoma cells treated with lapachol showed a dose-dependent inhibition of glycolysis and a corresponding increase in oxygen consumption. Accordingly, in silico studies revealed a high affinity-binding pocket for lapachol on PKM2 structure. Lapachol inhibited PKM2 activity of purified enzyme as well as in melanoma cell extracts. Blockade of glycolysis by lapachol in melanoma cells led to decreased ATP levels and inhibition of cell proliferation. Furthermore, perturbation of glycolysis in melanoma cells with lapachol sensitized cells to mitochondrial protonophore and promoted apoptosis. These results present lapachol as an inhibitor of PKM2 to interrogate metabolic plasticity in tumor cells.